Neuropathic Pain
Two cannabinoid receptors have been identified. CB1, present in the central nervous system (CNS) and to a lesser extent in other tissues, and CB2, present outside the CNS, in peripheral organs. There is evidence for the presence of CB2-like receptors in peripheral nerve terminals. In recent years there has been indirect evidence for the modulation of pain through CB2 receptor mechanisms. As a result, there has been an effort to develop and evaluate CB2-selective agonists such as HU308, AM1241, JWH-133, and GW405833. These compounds have provided support for the hypothesis that activation of CB2 produces antinociceptive effects in persistent pain states. Other compounds, CP55,940 and WIN55,212-2 are agonists that have high affinity for both CB1 and CB2 receptors and which also have been shown to suppress pain in animals. As with most cannabinoids, there is substantial evidence that these compounds cross the blood brain barrier (BBB). As a result, there are CNS side effects which may limit their use. The need exists for therapies and management of chronic to severe pain without the unwanted side effects.
Obesity
The cannabinoid rimonabant is approved in the European Union (as ACOMPLIA™) as an adjunct to diet and exercise for the treatment of obese patients that also have associated risk factors, such as type 2 diabetes or dyslipidaemia. Rimonabant is a selective cannabinoid CB1 receptor antagonist (or inverse agonist), with little or no affinity for other receptors. This interaction with peripheral CB1 receptors has been shown to reduce food intake and body weight when given acutely. There is substantial evidence that Rimonabant crosses the BBB. As a result, there are significant side effects which may limit its use.
Inflammation
The cannabinoid Dronabinol is currently used for chemotherapy-induced nausea and vomiting refractory to conventional antiemetics. Cannabinoids are being investigated for a number of other conditions including the treatment of inflammatory conditions like psoriasis. For this use, it is considered a Type 3 drug (centrally acting drug with potentially therapeutic peripheral activity).
Pharmacologically, cannabinoid drugs represent an important class of agents employed in the management of pain, obesity, inflammation, and also in combating drug addiction, alcohol addiction, smoking cessation, drug overdose, mental illness, urinary incontinence, cough, lung edema, diarrhea, depression, and cognitive, respiratory, and gastro-intestinal disorders, immunomodulation, migraine, asthma, epilepsy, glaucoma, Parkinson's disease, dyskinesia, neuropathy, memory and thymic disorders, vomiting, ischemia, angor, orthostatic hypotension, cardiac insufficiency, stress, anxio-depressive disorders or psychosomatic-induced disorders. However, administration of cannabinoid drugs results in significant side effects. Thus, a reduction of these side effects would enhance their desirability as therapeutic agents. As a consequence, there is a large unmet need for developing novel cannabinoid compounds.
The present invention seeks to address these and other needs in the art.